The emergence of in vivo resistance of Plasmodium falciparum malaria to standard antimalarial drugs is a major and growing threat to public health in Africa, Asia, and Latin America. Pregnant women and young children bear the brunt of this disease. The overall aim of this project is to add azithromycin to the antimalarial armamentarium. Azithromycin has already been shown in clinical trials to have substantial antimalarial activity as a single agent. However, several factors suggest that it will be best used in combination with a second antimalarial drug. A series of clinical trials will be conducted to demonstrate efficacy and safety of azithromycin drug combinations for malaria, including the special, at risk populations (children and pregnant women). Phase I clinical trials will be conducted to demonstrate safety. Phase II trials will be designed to demonstrated "proof of concept" and optimal dosage regimens. If Phase I and II trials are successful, these will be followed by pivotal Phase III studies of azithromycin in combination with two standard anti-malarial drugs. The research plan will lead to United States Food and Drug Administration approval of azithromycin as a drug combination of treatment of drug-resistant Plasmodium falciparum malaria. The trials should yield data to shown azithromycin as a safe drug combination for treatment of high-risk populations. AIM. Azithromycin, used as a practical drug combination, can achieve high efficacy in the treatment of drug resistant Plasmodium falciparum. 1. Test the hypothesis that efficacious azithromycin combinations are similarly safe and well tolerated as the standard anti-malarials alone in healthy volunteers (Phase I clinical trials). 2. Test the hypothesis that efficacious, well-tolerated treatment regimens can be identified through dose-ranging of standard anti-malarials in combination with azithromycin (Phase II "proof of concept"/dose-ranging clinical trials). 3. Test the hypothesis that the two most appropriate azithromycin drug combinations (i.e. azithromycin-quinine azithromycin-chloroquine) are safe and efficacious for curing drug-resistant malaria (Phase III pivotal trials). 4. Test the hypothesis that the best two azithromycin combinations are similarly efficacious in children and pregnant women (assess efficacy and safety in special populations).